title: Design, syntheses, and characterization of pharmacophore based chemokine receptor CCR5 antagonists as anti prostate cancer agents.
abstract: Accumulating evidence has shown multiple roles that chemokine receptor CCR5 may play to promote the progression of several types of cancer. The mechanism of such promotion is believed to involve chronic inflammation that creates a microenvironment which enhances tumor survival. Therefore, blocking CCR5 function with an antagonist may provide a novel treatment of cancers such as prostate cancer. Currently, several CCR5 antagonists are available, but all have been optimized for their inhibitory activity on HIV-1 cellular membrane invasion process rather than inhibition on cytoplasmic signaling pathways. Thus, there is need to develop CCR5 antagonists focusing on blockage of CCR5 downstream signaling and inhibition of CCR5 related prostate cancer proliferation and progression. In this report, a pharmacophore analysis was conducted based on docking studies of several known CCR5 antagonists in a CCR5 homology model. A unique structural skeleton for CCR5 antagonist was constructed and functionalized, resulting in a new series of small molecules to be synthesized and characterized. A combination of CCR5 calcium flux inhibition, anti prostate cancer cell proliferation, basal cytotoxicity, and in vivo animal model studies were applied to screen the newly synthesized compounds. Results from this study provided a potential lead compound for future CCR5 antagonist development focusing on prostate cancer therapy.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Arnatt
authors.forename: Saheem A
authors.initials: SA
authors.lastname: Zaidi
authors.forename: Zhu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Richardson
authors.forename: Joy L
authors.initials: JL
authors.lastname: Ware
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019713:Receptors, CCR5; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D019713:Receptors, CCR5
keywords: CCR5 antagonist; Pharmacophore based molecular design; Prostate cancer